~30 million people in the US have chronic kidney disease (CKD) and are at significantly increased risk of cardiovascular (CV) disease and mortality. One major mechanism contributing to increased CV risk in this patient population is chronic over-activation of the sympathetic nervous system (SNS). SNS overactivity in CKD leads to difficult-to-control blood pressure (BP), and an abnormal circadian rhythm of BP characterized by failure to decrease BP at night (i.e. nondipping), that is independently associated with increased CV risk. Current strategies to combat SNS overactivation, however, are limited to sympatholytic medications that are often poorly tolerated with adverse side effects. Therefore, there is a critical need to develop novel, safe, and well-tolerated strategies for reducing SNS activity to improve clinical CV outcomes in this highly prevalent and growing population of CKD patients. One such novel approach at improving hemodynamics and autonomic function in CKD is mindfulness meditation (MM). Multiple prior studies have shown that MM, and specifically mindfulness-based stress reduction (MBSR), significantly reduces BP in a variety of patient populations. However, the mechanisms underlying the BP-lowering effect of MM are unclear. Small studies using indirect measures have suggested that MM may modulate the autonomic nervous system; however, no prior studies have used direct, gold-standard methods to interrogate the sustained effects of MM-based interventions on SNS. We performed the first studies using direct, intraneural measurements of muscle sympathetic nerve activity (MSNA) that demonstrate that MM acutely reduces BP and MSNA in CKD. In Aim1 (R61), we will test the hypothesis that 8 weeks of MBSR leads to sustained reductions in MSNA that are linked to improvements in daytime BP, and improved nocturnal dipping of BP in CKD. Following these studies, we will determine if transcutaneous vagus nerve stimulation (tVNS), a simple, noninvasive, self-administered adjunctive therapy, enhances the sympatho-inhibitory effects of MM in CKD. The vagus nerve, the major effector of the parasympathetic nervous system (PNS), is comprised of afferent nerve fibers that connect to the nucleus tractus solitarii (NTS) and other brainstem regions that influence central SNS output and baroreflexes, and efferent nerve fibers that activate the cholinergic anti-inflammatory pathway. Both experimental and human studies have demonstrated that tVNS reduces SNS activity, improves baroreflex sensitivity (BRS), and lowers inflammation, and our preliminary data demonstrate that tVNS reduces MSNA and improves BRS in CKD. In Aim 2 (R33), we will test the hypothesis that tVNS augments the beneficial effects of MBSR on MSNA and ambulatory BP profiles, and ameliorates SNS overactivation by improving arterial BRS and reducing inflammation in CKD. These studies will elucidate autonomic mechanisms underlying the beneficial effects of MM in CKD, while addressing a critical need for the development of safe, well-tolerated and effective treatment approaches to ameliorating SNS overactivity, reducing BP and improving CV risk profiles in patient with CKD.